Inhibiting fungal growth with 2-benzimidazole alkyl carbamates

ABSTRACT

Compounds corresponding to the formula   WHEREIN R1 is selected from alkoxy and alkoxyalkyl; R2 is selected from alkyl, aryl, alkenyl, thioalkyl, alkylaryl, haloalkyl, cycloalkyl, haloalkenyl, alkoxyalkyl, alkenylaryl, furanyl and carboalkoxy are useful as fungicides.

United States Patent Baker et al.

INHIBITING FUNGAL GROWTH WITH Z-BENZIMIDAZOLE ALKYL CARBAMATES Inventors: Don R. Baker, Orinda; Julius J.

Menn, Saratoga; Ashley H. Freiberg, Santa Clara, all of Calif.

Staufler Chemical Company, New York, NY.

Filed: Sept. 3, 1971 Appl. No.: 177,872

Related US. Application Data Division of Ser. No. 30,984, April 22, 1970, Pat. No. 3,658,812.

Assignee:

US. Cl. 424/273 int. Cl. A6lk 27/00, A01n'9/22 Field of-Search 424/273 References Cited UNITED STATES PATENTS ll/l970 Klopping 424/273 Oct. 9, 1973 Primary Examiner-Albert T. Meyers Assistant Examiner-Frederick E. Waddell Attorney-Daniel C. Block et al.

[5 7 1 ABSTRACT Compounds corresponding to the formula 4 Claims, No Drawings INHIBITING FUNGAL GROWTH WITH Z-BENZIMIDAZOLE ALKYL CARBAMATES This is a division of U.S. Pat. application Ser. No. 30,984 filed Apr. 22, 1970, now U.S. Pat. No. 3,658,812.

DESCRIPTION OF THE INVENTION The present invention is concerned with a novel group of compounds which can be generally described as 2-benzimidazole carbamates, and their use as pesticides, especially effective against fungi and parasites.

The compounds are represented by the general formula wherein, R, is selected from alkoxy and alkoxyalkyl; R is selected from alkyl, aryl, alkenyl, thioalkyl, alkylaryl, haloalkyl, cycloalkyl, haloalkenyl, alkylalkoxy, a1- kenylaryl, furanyl, and carboalkoxy.

The compounds represented by the above formula can exist in two tautomeric forms as follows:

wherein R and R have been previously defined.

The compounds represented by the above general formulae are manufactured by reacting a 2- benzimidazole alkyl carbamate in an inert solvent with an acid chloride or other like material in the presence of an acid acceptor. The inert solvent can be selected from benzene, chloroform, or the like. The acid acceptor can be selected from triethyamine, pyridine, or the like. ln order to illustrate the merits of the present invention, the following examples are provided.

EXAMPLE 1 1-n-heptanoyl-2-benzimidazole methyl carbamate A mixture was formed containing 9.5 gm. of 2- benzimidazole methylcarbamate in 100 ml. chloroform. Then 7.4 gm. of heptanoyl chloride was added followed by the dropwise addition of 7 ml. of triethylamine. A solid still remained so another 7.4 gm. of the acid chloride and 7.0 ml. of triethylamine was added portionwise with stirring at 20 to 30 C. After the addition was completed, the mixture was stirred for one hour, washed with 150 ml. water, sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to yield an oil that crystallized from cold n-pentane to yield 12.9 gm. of the solid compound, having a melting point of between 78 and 80 C.

EXAMPLE ll Cyclohexylcarbonyl-2-benzimidazole carbamic acid,

methyl ester A mixture of 9.5 gm. of 2-benzimidazole methyl carbamate and ml. of chloroform was made. Then, 7.3 gm. of cyclohexane carbonyl chloride was added followed by dropwise addition of 7 ml. of triethylamine over a period of 30 minutes at 22 to 30 C. with stirring. The mixture was stirred for an additional 30 minutes and then washed with 50 ml. of water and filtered. The chloroform portion was dried over magnesium sulfate and evaporated in a vacuum to yield 9.2 gm. of a solid having a melting point of to C.

EXAMPLE Ill l-benzoy1-2-benzimidazole carbamic acid methyl ester A 7 ml. portion of triethylamine was added to a mixture of 9.5 gm. of 2-benzimidazo1e methylcarbamate, 100 ml. of chloroform and 8.5 ml. of benzoylchloride over a period of 15 minutes, at 20 to 26 C. After 1 hour, the reaction was still not complete so it was stirred overnight (16 hours). The mixture was diluted with water, filtered, and the chloroform solution was evaporated and dried over magnesium sulfate to give an oil that was washed with ethyl-ether to yield 8.4 gm. of a solid, having a melting point of 140 to 147 C.

Other compounds were prepared in an analogous manner starting with the appropriate starting materials, as outlined above. The following is a table of compounds representative of those embodied by the present invention. Compound numbers have been assigned to them and are used for identification throughout the balance of the specification.

TABLE 1 TABLE IContinued 9 OCH, cng

l ocn. CH2C H-CHg-l-CH;

1 l ocn cci=ccl, 12 ocH cmocn l3 ocn, oHFc CH3 1 4 ocl-il CH,Cl l5 ocn ca, 16 OCH, CF, l7 OCH; I)s

l8 ocn amon -G FUNGlClDE TESTING PROCEDURES A. Foliar Preventative Sprays 1. Bean Rust 7 The chemicals are dissolved in an appropriate solvent and diluted with water containing several drops of Tween-20, a wetting agent. Test concentrations, rang ing from 1,000 ppm downward, are sprayed to runoff on the primary leaves of pinto beans (Phaseolus vulgaris L.). After the leaves are dried, they are inoculated with a water suspension of spores of the bean rust fungus (Uromyces phaseoli Arthur) and the plants are placed in an environment of 100 percent humidity for 24 hours. The plants are then removed from the humidity chamber and held until disease pustules appear on the leaves. Effectiveness is recorded as percent reduction in number of pustules as compared to untreated inoculated plants.

2. Bean Powdery Mildew Test chemicals are prepared and applied in the same manner as for the bean rust test. After the plants are dry, the leaves are dusted with spores of the powdery mildew fungus (Erysiphe polygoni De Candolle) and the plants are retained in the greenhouse until the fungal growth appears in the leaf surfaces. Effectiveness is recorded as percent of the leaf surface free of fungal growth as compared to untreated inoculated plants. B. Foliar Eradicative Sprays 1. Bean Powdery Mildew Untreated pinto bean plants are dusted with spores of the powdery mildew fungus and maintained in the greenhouse until mycelial growth appears in the leaf surface. Test chemicals are then prepared and applied in the same manner as for the preventative spray test. Four days later the leaves are examined for inhibition of further mycelial growth. Eradicative effectiveness is recorded as the percentage ofinhibition of viable, sporulating mycelium as compared to untreated inoculated plants. C. Tube Systemic Test 1. Bean Rust I The chemicals are dissolved in an appropriate solvent and diluted with tap water to a series of descending concentrations beginning at 50 ppm. ml. of each concentration are placed in a test tube. A pinto bean plant is placed in each tube and supported with a piece of cotton so that only the roots and lower stem are in contact with the test solution. 48 hours later the bean leaves are inoculated with a water suspension of spores of the bean rust fungus and placed in an environment with 100 percent humidity for 24 hours. The plants are then removed from the humidity chamber and maintained in the greenhouse until the disease pustules appear on the leaves. Effectiveness is recorded as the lowest concentration, in ppm, which will provide 50 percent reduction in pustule formation as compared to untreated, inoculated plants.

2. Bean Powdery Mildew Test chemicals are prepared and applied in the same manner as for the bean rust systemic test. After 2 days the leaves are dusted with spores of the powdery mildew fungus and maintained in the greenhouse until mycelial growth appears in the leaf surfaces. Effectiveness is recorded as the lowest concentration, in ppm, which will provide a 50 percent reduction in mycelial growth on the leaf surface as compared to untreated, inoculated plants.

BlOCIDE TESTING PROCEDURES Tubes of sterilized nutrient and malt extract broth are prepared. Aliquots of the toxicant, dissolved in an appropriate solvent, are injected through the stopper, into the broth, to provide concentrations ranging from 50 ppm downward. The test organisms consist of two fungi, Aspergillus niger (A.n.) van Tieghem and Penicillium italicum (P.i.) Wehmer, and two bacteria, Escherichia coli (12.0.) Migula and Staphylococcus aureus (8.2.) Rosenbach. Three drops of a spore suspension of each of the fungi are injected into the tubes of malt broth and three drops of the bacteria are injected into the nutrient broth. One week later the growth of each organism is observed and effectiveness of the chemical is recorded as the lowest concentration in ppm which provides 50 percent inhibition of growth as compared to' untreated inoculated tubes.

The results of the above tests are set forth in the following table.

TABLE II Preventative sprays, p.p.rn.

Mildew eradica- Tube systemic, In vitro vial (p.p.m.) Rust, Mildew tive sprays, ppm. p.p.m. Compound number A.n. P.i. E.c. S a 1,000 500 100 1,000 500 100 50 25 10 1,000 500 100 Rust Mildew TABLE IICntinued Preventative sprays, p.p.m.

. Mildew eradica- Tube s siemic, In vitro vial (p.p.m.) Rust Mildew tivo sprays, p.p.1n. prim. Compound .2. number A.n. P.i. E.c. 5.21. 1,000 500 100 1,000 500 100 50 10 1,000 500 100 Rust lllildew 10 0.13 50 50 100 100 95 100 100 50 .25 0 5 0 13 5 0. 05 50 50 75 50 0 00 09 0 0 0 5 5 0. 06 50 50 99 75 25 .15 80 25 (l 0 5 l) .25 5 0. 03 50 50 100 08 80 100 00 25 0 0 5 u: 13 5 0.13 50 50 100 100' 75 100 100 25 0 t) 5 1 0 5 0. 00 50 50 08 05 58 100 100 25 0 0 5 11 0 ANTHELMINTIC TESTING METHODS I. Feed testing:

Combined observations of safety and efficacy of compounds fed continuously in the diet of mice were made against: Nematospiroides dubius (Nd), a nonmigrating trichostrongyle nematode; Nippostrongylus muris (Nm), a migrating trichostrongyle nematode; Syphacia obvelata (So), a cecal pinworm; Aspiculuris tetraptera (At), an intestinal pinworm; and Hymenolepis nana (Hn), an intestinal tapeworm.

The experimental compounds were weighed out in specific amounts, premixed with powdered feed in a mortar and pestle, and blended in a power mixer for '30 to 40 minutes.

Yound Swiss Webster mice (12 to 24 g body Weight) were obtained from local animal husbandry centers and housed in pairs in hardware cloth cages. These mice were put on medicated rations supplied in tared wasteproof containers two days prior to inducing infections. Drinking water was supplied ad lib in drip bottles. Feed consumption and weight variations were recorded after the first week to assess subclinical toxicity and palatibility.

After 21 days on medicated feed, mice were necropsied and the parasites remaining in the entire small intestine, cecum, and colon counted and differentiated. This was done by compressing the intestinal tract between two 3 inch X 4 inch glass plates and examining them under low power magnification. The average number of each species remaining in the medicated groups was compared to average numbers of each species in controls. This figure was then subtracted from 100 percent to yield the percent efficacy.

II. Oral dose testing:

This test was conducted under the same protocol as the feed test, except: V

1. The helminth infections were administered 21 days prior to drug administration.

2. The experimental compounds were formulated as solutions in Tween 20 and administered orally by stomach tube in mg/kg dosages.

3. The sacrifice of the mice was carried out 1 to 3 days following drug administration, and the results are therefore indicative of therapeutic activity.

The results of the above tests are set forth in Table III.

T113515 in 15 P.p.n1. Percent eflicacy Compound or lethal number to mice Nd N111 1111 So At *MgJkg. body weight.

What is claimed is: 1. A method of controlling fungi comprising applying to the habitat thereof an effective fungal inhibiting amount of a compound of the formula:

wherein R is methoxy; R is selected from the group consisting of furanyl, styryl and benzyl.

2. The method of claim 1, wherein R is styryl.

3. The method of claim 1, wherein R is furanyl. 4. The method of claim 1, wherein R, is benzyl.

I! i l 3 

2. The method of claim 1, wherein R2 is styryl.
 3. The method of claim 1, wherein R2 is furanyl.
 4. The method of claim 1, wherein R2 is benzyl. 